As a result of extensive studies of excitatory mechanisms in the central nervous system (CNS) during the past three decades, there is now a consensus of opinion that (S)-glutamate (Glu) is the major EAA neurotransmitter in the CNS (Lodge, D. Excitatory Amino Acids in Health and Disease. J. Wiley & Sons: Chichester, 1988; Wheal, H.; Thomson, A. Excitatory Amino Acids and Synaptic Transmission. Academic Press: London, 1991; Meldrum, B. S. Excitatory Amino Acid Antagonists. Blackwell Sci. Publ.: Oxford, 1991; Krogsgaard-Larsen, P.; Hansen, J. J. Excitatory Amino Acid Receptors: Design of Agonist and Antagonists. E. Horwood: Chichester, 1992). Glu-operated neurotransmission is mediated by a large number of receptors, classified into at least four heterogeneous families of receptors named NMDA, AMPA, kainic acid, and metabotropic classes of receptors (Monaghan, D. T., et al. Ann. Rev. Pharmacol. Toxicol. 1989,29, 365-402; Watkins, J. C.; Krogsgaard-Larsen, P.; Honore, T. Trends Pharmacol. Sci. 1990,11, 25-33; Simon, R. P. Excitatory Amino Acids. Thieme Med. Publ.: New York, 1992).
There is very strong evidence supporting the view that excessive excitation mediated by EAA receptors ("excitotoxicity") is a factor of major importance in cerebral ischaemia following stroke, head injury, asphyxia, subarachnoid haemorrhage, cardiac arrest and other situations (Lodge, D., 1988 supra; Meldrum, B. S., 1991 supra). It has been shown in animal models that the damages caused by various ischaemic conditions can be inhibited by the administration of Glu-antagonists. So, although the relative importance of the different classes of EAA receptors in the phenomena underlying ischaemic insults is unclear, it is generally agreed that EAA receptor antagonists are potential therapeutic agents in these conditions.
Accumulating evidence derived from different lines of neurochemical and pharmacological research suggests that derailed EAA receptor mechanisms, possibly including "excitotoxicity", play a role in Huntington's disease (Young, A. B.; et al. Science 1988,241, 981-983), epileptic disorders (Krogsgaard-Larsen, P.; Hansen, J. J., 1992 supra), Parkinson's disease (Klockgether, T.; Turski, L. Trends. Neurosci. 1989,12, 285-286), and Alzheimer's disease (Greenamyre, J. T.; Maragos, W. F. Cerebrovasc. Brain. Metab. Rev. 1993,5, 61-94; Francis, P. T., et al. J. Neurochem. 1993,60, 1589-1604).
Furthermore, central EAA receptors may be involved in the synaptic mechanisms underlying schizophrenia (Reynolds, G. P. Trends. Pharmacol. Sci. 1992,13, 116-121), pain and anxiety (Drejer, J. In: Excitatory Amino Acid Receptors: Design of Agonists and Antagonists (Eds. Krogsgaard-Larsen, P.; Hansen, J. J.) E. Horwood: Chichester 1992, pp. 352-375) and depression (Trullas, R., Skolnick, P., Eur. J. Pharmacol. 1990, 185, 1-10 and Trullas et al., Eur. J. Pharmacol. 1991, 203, 379-385. So, reduced function of EAA receptors (EAA hypoactivity) seems to play a role in, for example, schizophrenia (Deutsch, S. I.; et al. Clin. Neuropharmacol. 1989,12, 1-13) and some of the clinical symptoms seen in Alzheimer's disease (Greenamyre, J. T.; et al. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988,12, 421-430). It is possible that "excitoxicity" as well as EAA hypoactivity are involved in the complex mechanisms associated with Alzheimer's disease (Greenamyre, J. T.; 1988 supra; Greenamyre, J. T.; Maragos, W. F., 1993, supra).
Accordingly, EEA receptor ligands are considered to be useful in the treatment of cerebral ischaemia, Huntington's disease, epileptic disorders, Parkinson's disease, Alzheimer's disease, anxiety, schizophrenia, depression and pain.
Most EAA receptor agonists so far tested, show more or less pronounced neurotoxicity in model systems and consequently clinical uses of such compounds may be limited (Carlsson, M.; Carlsson, A. Trends. Neurosci. 1990,13, 272-276) (Willetts, J.; Balster, R. L.; Leander, J. D. Trends. Pharmacol. Sci. 1990,11,423-428).
Partial EAA agonists showing appropriate balance between agonism and antagonism may, on the other hand, have considerable therapeutic interest, cf. the above indications, (Greenamyre, J. T.; 1988 supra; Christensen, I. T.; et al. Drug. Des. Del. 1989,5, 57-71; Francis, P. T.; et al. J. Neurochem. 1993,60, 1589-1604). Partial agonists may, by virtue of their EAA antagonist profile, show therapeutically useful neuroprotection and, at the same time, be sufficiently agonistic to prevent total blockade of the neurotransmission mediated by the particular EAA receptor.
ATPA, the 5-tert-butyl analogue of AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid), has been disclosed to be systemically active whereas it has not been reported to show neurotoxic effects in animals (Ornstein, P. L.; et al. J. Med. Chem. 1993,36, 2046-2048; Lauridsen, J.; Honore, T.; Krogsgaard-Larsen, P. J.Med.Chem. 1985, 28, 668-672).
Like AMPA itself, a number of mono- and bicyclic AMPA analogues have been found to show selective agonist effects at AMPA receptors (Hansen, J. J.; Krogsgaard-Larsen,P. Med. Res. Rev. 1990,10, 55-94; Krogsgaard-Larsen, P.; Hansen, J. J., 1992 supra;). One of these analogues, (RS)-2-Amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA), in which the methyl group of AMPA has been replaced by a phenyl group, shows a weak but unique partial agonist profile (Christensen, I. T.; et al., 1989, supra).
ACPA ((RS)-2-amino-3-(3-carboxyoxy-5-methylisoxazol-4-yl)propionic acid) has been described as a potent AMPA receptor agonist (Madsen, U. and Wong, E. J. Med. Chem. 1992,35, 107-111).
Furthermore, WO-A1 95012587 discloses a class of (5-arylisoxazol-4-yl)- or (5-arylisothiazol-4-yl)-substituted 2-amino carboxylic acid compounds as EAA-receptor ligands.
As seen from the above non-neurotoxic, CNS-active EEA receptor ligands with good penetration into the CNS are highly desirable for treating the various diseases mentioned and, accordingly, it is the object of the present invention to provide such new drugs.